Non-nucleoside HIV-1 reverse transcriptase inhibitors. Part 13: Synthesis of fluorine-containing diaryltriazine derivatives for in vitro anti-HIV evaluation against wild-type strain

Article abstract of DOI:10.1002/cbdv.200800163

A series of diaryltriazine derivatives modified at C(2) of the triazine ring with a fluorinated phenyl group has been synthesized and tested for the ability to inhibit HIV-1 replication. Most of these F-containing compounds showed low-to-moderate anti-HIV

Full text of DOI:10.1002/cbdv.200800163

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561
Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors
Part 131)
Synthesis of Fluorine-Containing Diaryltriazine Derivatives for in vitro Anti-HIV
Evaluation against Wild-Type Strain
by Yuan-Zhen Xionga), Fen-Er Chen*a)b)c), Jan Balzarinid), Erik De Clercqd), and
Christophe Pannecouqued)
a) School of Pharmacy, Fudan University, Shanghai 200031, P. R. China
(phone: þ86-21-65643811; fax: þ86-21-65643811; e-mail: rfchen@fudan.edu.cn)
b) Department of Chemistry, Fudan University, Shanghai 200433, P. R. China
c) Institute of Biomedical Science, Fudan University, Shanghai 200031, P. R. China
d) Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven
A series of diaryltriazine derivatives modified at C(2) of the triazine ring with a fluorinated phenyl
group has been synthesized and tested for the ability to inhibit HIV-1 replication. Most of these F-
containing compounds showed low-to-moderate anti-HIV activity in MT-4 cells.
Introduction. – The reverse transcriptase (RT) of human immunodeficiency virus
type 1 (HIV-1) is a multifunctional key enzyme. The inhibition of RT is considered as
one of the most valuable and practicable approaches to suppress AIDS spreading.
Subsequent to the discovery of diaryltriazine analogues (DATAs) as a class of novel
potent and selective compounds for non-nucleoside reverse transcriptase inhibitors
(NNRTIs) of HIV-1 [2–5], attention has been focused on the alteration of the
substitution at C(4) and C(6) of the triazine nucleus in DATAs, leading to the synthesis
of novel DATA analogues, 1–3, with potency against HIV-1 replication. However,
there are unexplored aspects in changing the functionality in the phenyl ring moiety at
C(2).
It is well-known that the introduction of F substituents to biologically active
substances, especially incorporating a F-atom into an aromatic or heterocyclic ring, can
1
)
For Part 12, see [1].
ꢀ 2009 Verlag Helvetica Chimica Acta AG, Zꢁrich

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affect their biological properties associated with lipophilicity, absorption, and trans-
portation because of the highest electronegativity, high thermal stability, and
lipophilicity [6]. As part of our continuing interest in DATA series as NNRTIs [2],
we direct our attention to investigate whether or not introduction of a F-atom into a
phenyl ring at C(2) of a triazine skeleton will impact the antiviral activity. Herein, the
synthesis, biological evaluation, and preliminary SAR profile of fluorinated DATA
congeners 4 are described.
Results and Discussion. – 1. Chemistry. The typical synthetic routes for the title
compounds are outlined in Schemes 1 and 2. Condensation of 2,4,6-trichloro-1,3,5-
triazine with 4-amino-3-fluorobenzonitrile gave the key intermediate 6 according to the
protocol described in [2]. Nucleophilic substitution of 6 by different b-naphthols
(¼ naphthalen-2-ols) and p-cresol (¼4-methylphenol) in the presence of 60% NaH at
50–608 provided 7a–7c and 9, respectively, in 50–55% yield. Treatment of 7a–7c with
appropriate primary amines in 1,4-dioxane at 60–708 afforded the desired DATA
analogues 8a–8n in 40–50% yield (Scheme 1). Further target compounds, 10a–10e,
were conveniently synthesized by reaction of 9 with the corresponding amines in 1,4-
dioxane at 60–708 (Scheme 2). All synthesized compounds were characterized by
spectroscopic data as IR, MS, and NMR.
Scheme 1
a) 4-Amino-3-fluorobenzonitrile, Et3N, anh. THF, 0–58, 4.5 h. b) b-Naphthols (¼ naphthalen-2-ols),
60% NaH, anh. THF, N2, 50–608, 4.5 h. c) R2NH2, 1,4-dioxane, 60–708, 1–4 h.
2. Biological Activities. The novel fluorinated DATA derivatives synthesized in this
study are evaluated for their inhibitory activity against HIV-1 IIIB strains including

CHEMISTRY & BIODIVERSITY – Vol. 6 (2009)
563
Scheme 2
a) 4-Amino-3-fluorobenzonitrile, Et3N, anh. THF, 0–58, 4.5 h. b) p-Cresol (¼4-methylphenol), 60%
NaH, anh. THF, N2, 50–608, 4.5 h. c) NH3 or R2NH2, 1,4-dioxane, 60–708, 1–4 h.
cytopathology in MT-4 cell using the MTT2) method [7]. The results are listed in the
Table, together with the antiviral data of 2’,3’-dideoxyinosine (DDI) and 1-[(2-
hydroxyethoxy)methyl]-6-(phenylsulfanyl)thymine (HEPT), which are included in
the Table for comparison.
As seen from the Table, most of the newly synthesized F-containing DATA
analogues were active against HIV-1 replication with a wide range of IC50 values from
18.3ꢀ8.05–0.36ꢀ0.067 mm; two compounds, 8e and 8f, endowed with IC50 values of
0.36 and 0.41 mm, respectively, were almost 14-fold higher in activity than DDI.
However, these analogs showed less potency compared with the corresponding
compounds reported in the literature [2]. In addition, the effect of the substituent at
C(6) of the triazine ring was examined; it was found that all compounds with a
substituent on the naphthyl or the phenyl ring were potent against wild-type HIV-1,
whereas compounds 8a–8d without any substitution on the naphthyl ring were devoid
of any antiviral activity, indicating that increasing volume of the substituent at C(6) of
the triazine ring might be beneficial for strengthening p–p stacking interaction
between inhibitors and Tyr188 or Tyr181 of RT. The nature of the substituent at C(4) of
the nuclei plays an important role in the inhibitory activity as previously observed [2].
It is worth nothing that the alkylation of the amino group at C(4) with different alkyl
group such as Et, Pr, i-Pr provided N-alkylated derivatives which were less potent than
their counterparts, for example, as in case of 8i, the potency of which was 22-fold lower
compared to that of 8f. Interestingly, most of the compounds were endowed with a CC50
value higher than 240 mm except five compounds, i.e., 8e, 8f, 8j, 10b, and 10d (CC50 98–
180 mm).
Conclusions. – A series of novel DATA analogues with F-substituent was
synthesized and evaluated for their anti-HIV activities. The bioassay results demon-
strated that most of the compounds show inhibitory potency against HIV-1.
This work was supported by a grant from the National Science Foundation of China (No. 30672536).
2
)
MTT¼3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium hydrobromide.

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CHEMISTRY & BIODIVERSITY – Vol. 6 (2009)
Table. Anti-HIV-1 Activity of DATA Derivatives in MT-4 Cells. For details, see Exper. Part.
Drug
R1
R2
HIV-1 IIIB IC50 [mm]a)
CC50 [mm]b)
SIc)
<1
<1
<1
8a
8b
8c
H
H
H
Me
H
Et
236
336
222
236
336
222
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
10a
10b
10c
10d
10e
DDId)
HEPTe)
H
allyl
Me
H
229
229
98.84
<1
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
0.36ꢀ0.067
0.415ꢀ0.042
2.05ꢀ1.06
1.173ꢀ0.096
9.49ꢀ2.09
0.802ꢀ0.41
0.709ꢀ0.187
1.618ꢀ0.014
1.98ꢀ0.37
4.911ꢀ0.78
2.884ꢀ0.54
1.078ꢀ1.36
8.89ꢀ0.74
4.35ꢀ1.38
18.3ꢀ8.56
5.37
274
543
>128
>218
>27
186
354
>167
140
>57
86
109.91
>261.51
>255.1
>254.07
148.95
251.58
>269.58
280.27
>279.02
247.76
162.68
243.19
185.62
278.38
ꢂ529
Et
allyl
iPr
Me
H
Et
allyl
Pr
Me
H
Et
Pr
iPr
151
27
43
15
ꢂ98
5.06
405
80
a) ꢂInhibitory Concentration fiftyꢃ: drug concentration required to protect the cell against viral
cytopathogenicity by 50% in MT-4 cells. b) ꢂCytotoxic concentration fiftyꢃ: drug concentration reducing
c
the normal uninfected in MT-4 cell viability by 50%. ) ꢂSelectivity indexꢃ: SI¼CC50/IC50. d) DDI¼2’,3’-
e
dideoxyinosine (positive control). ) HEPT¼1-[(2-hydroxyethoxy)methyl]-6-(phenylsulfanyl)thymine.
Experimental Part
General. All chemicals and solvents were reagent-grade and purified by standard methods prior to
use. M.p.: WRS-1 digital melting-point apparatus; uncorrected. IR Spectra (KBr): Jasco FT/IR-4200
.
instrument; in cmꢁ1 1H- and 13C-NMR spectra: Bruker AV 400 MHz spectrometer; chemical shifts
expressed in ppm downfield from Me4Si, which was used as an internal standard. MS: Agilent MS/5975
mass spectrometer; in m/z.
Preparation of 4-[(4,6-Dichloro-1,3,5-triazin-2-yl)amino]-3-fluorobenzonitrile (6). To a stirred soln.
of 2,4,6-trichloro-1,3,5-triazine (5; 7.28 g, 0.04 mol) in anh. THF (100 ml) was added 4-amino-3-
fluorobenzonitrile (5.38 g, 0.04 mol) dropwise at 0–58 under N2. The resulting soln. was stirred at this
temp. for 1 h, and Et3N (3.03 g, 0.04 mol) was added into the mixture. Stirring was continued for another
h. The precipitate was collected by filtration, washed with H2O, and dried to afford 6 (5.38 g, 65%). Off-
white solid. M.p. 285.38 (dec.). FT-IR (KBr): 2220 (CN). 1H-NMR (CDCl3): 7.41–7.80 (m, 3 arom. H);
10.80 (s, NH). EI-MS: 283 (Mþ ).

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565
General Procedure for the Preparation of the Target Compounds 7a–7c. To a stirred soln. of the
appropriate naphthalen-2-ol (11.3 mmol) in anh. THF (100 ml) was added 60% NaH (0.452 g,
11.3 mmol) at r.t. under N2. The resulting soln. was stirred at this temp. for 30 min, and 6 (3.03 g,
11.3 mmol) was added to the mixture. Stirring was continued for another 4 h at 50–608. The precipitate
was collected by filtration, washed with H2O, and recrystallized from MeOH to afford the desired
products 7a–7c.
4-({4-Chloro-6-[(naphthalen-2-yl)oxy]-1,3,5-triazin-2-yl}amino)-3-fluorobenzonitrile (7a). Yield:
1
2.23 g (50%). Off-white solid. M.p. 1528 (dec.). H-NMR (CDCl3): 7.42–8.08 (m, 10 arom. H); 10.87
(s, 1 H, NH). 13C-NMR (CDCl3): 108.1 (CN); 117.4; 118.3; 119.6; 120.1; 121.0; 121.2; 125.9; 126.1; 126.3;
127.0; 127.7; 128.1; 129.8; 129.9; 134.0; 147.0 (Ar); 165.7; 170.6; 170.8 (triazine). EI-MS: 391 (Mþ ).
4-({4-[(1-Bromonaphthalen-2-yl)oxy]-6-chloro-1,3,5-triazin-2-yl}amino)-3-fluorobenzonitrile (7b).
Yield: 2.60 g (49%) Off-white solid. M.p. 1708 (dec.). 1H-NMR (CDCl3): 7.52–8.27 (m, 9 arom. H);
10.84 (s, NH). 13C-NMR (CDCl3): 104.4 (CN); 114.1; 117.2; 119.3; 119.9; 121.8; 122.7; 123.9; 125.7; 126.0;
127.2; 128.1; 129.8; 131.5; 132.1; 147.0 (Ar); 165.9; 169.9; 170.8 (triazine). EI-MS: 471 (Mþ ).
4-({4-Chloro-6-[(1-chloronaphthalen-2-yl)oxy]-1,3,5-triazin-2-yl}amino)-3-fluorobenzonitrile (7c).
1
Yield: 2.40 g (50%). Off-white solid. M.p. 213.88 (dec.). H-NMR (CDCl3): 7.52–8.27 (m, 9 arom. H);
10.98 (s, NH). 13C-NMR (CDCl3): 104.7, 114.5, 117.1, 120.0, 121.2, 121.7, 122.3, 124.6, 126.9, 128.4, 128.7,
129.2, 129.8, 130.1, 131.8, 139.3, 145.1 (Ar); 165.6, 169.0, 170.5 (triazine). EI-MS: 425 (Mþ ).
General Procedure for the Preparation of Compounds 8a–8n. Amine R2NH2 (5.48 mmol) was added
to a soln. of 7a–7c (1.37 mmol) in 1,4-dioxane (150 ml) at r.t. under stirring. The resulting soln. was
stirred at 60–708 for 1–4 h, and then precipitation took place. The solid was collected by filtration,
dissolved in AcOEt (20 ml), washed with 4% NaOH (1ꢃ10 ml), sat. aq. NaHCO3 soln (3ꢃ20 ml), and
brine (3ꢃ20 ml), and dried (MgSO4), and the org. layer was concentrated in vacuo at 808 to give crude
products, which were recrystallized from MeCN to afford 8a–8n.
3-Fluoro-4-({4-(methylamino)-6-[(naphthalen-2-yl)oxy]-1,3,5-triazin-2-yl}amino)benzonitrile (8a).
Yield: 0.26 g (50%). Off-white solid. M.p. 245.38(dec.). 1H-NMR (CDCl3): 2.76 (dd, J¼4.0, Me);
7.31–8.14 (m, 10 arom. H); 9.45 (s, MeNH); 9.65 (s, NH). 13C-NMR (CDCl3): 27.3 (Me); 105.4 (CN);
118.3, 119.0, 122.2, 124.6, 125.5, 126.2, 127.2, 128.4, 128.6, 129.3, 130.5, 132.0, 133.4, 149.7 (Ar); 165.3,
167.0, 170.8 (triazine). EI-MS: 386 (Mþ ).
4-({4-Amino-6-[(naphthalen-2-yl)oxy]-1,3,5-triazin-2-yl}amino)-3-fluorobenzonitrile (8b). Yield:
1
0.25 g (50%). Off-white solid. M.p. 2708 (dec.). H-NMR (CDCl3): 7.17–8.14 (m, 10 arom.H); 9.55 (s,
NH); 13C-NMR (CDCl3): 105.7 (CN); 118.3, 119.4, 122.2, 125.1, 125.5, 126.5, 127.4, 127.6, 128.5, 128.6,
129.2, 130.8, 133.5, 149.8, 151.8, 154.3 (Ar); 166.9, 168.3, 171.1 (triazine). EI-MS: 372 (Mþ ).
4-({4-(Ethylamino)-6-[(naphthalen-2-yl)oxy]-1,3,5-triazin-2-yl}amino)-3-fluorobenzonitrile (8c).
1
Yield: 0.27 g (51%). Off-white solid. M.p. 195.98(dec.). H-NMR (CDCl3): 1.02–1.08 (m, Me); 3.16–
3.38 (m, CH2); 7.33–8.10 (m, 10 arom. H); 9.44 (s, EtNH); 9.60 (s, NH). 13C-NMR (CDCl3): 105.4 (CN);
117.7, 118.2, 119.2, 122.2, 124.7, 125.5, 126.2, 127.2, 127.7, 128.5, 129.2, 131.0, 132.0, 133.7, 149.8, 151.8 (Ar);
165.3, 166.6, 170.6 (triazine). EI-MS: 400 (Mþ ).
3-Fluoro-4-({4-[(naphthalen-2-yl)oxy]-6-[(prop-2-en-1-yl)amino]-1,3,5-triazin-2-yl}amino)benzoni-
1
trile (8d). Yield: 0.28 g (51%). Off-white solid. M.p. 174.88 (dec.). H-NMR (CDCl3): 3.79–3.87 (m,
CH2CH¼CH2); 5.01–5.15 (m, CH2CH¼CH2); 5.77–5.82 (m, CH2CH¼CH2); 7.31–8.12 (m, 10 arom.
H); 9.58 (s, NH). 13C-NMR (CDCl3): 15.1 (CH2CH¼CH2); 42.5 (CH2CH¼CH2); 64.8 (CH2CH¼CH2);
105.5 (CN); 115.4, 118.3, 119.2, 122.1, 124.8, 125.2, 125.5, 126.4, 126.8, 127.3, 128.4, 129.0, 131.1, 131.9,
133.6, 135.1, 149.7, 151.5, 154.2 (Ar); 165.2, 167.0, 170.6 (triazine). EI-MS: 412 (Mþ ).
4-({4-[(1-Bromonaphthalen-2-yl)oxy]-6-(methylamino)-1,3,5-triazin-2-yl}amino)-3-fluorobenzoni-
trile (8e). Yield: 0.31 g (48%). Off-white solid. M.p. 220.48 (dec.). 1H-NMR (CDCl3): 2.50 (s, Me); 7.64–
8.26 (m, 9 arom. H); 8.53 (s, MeNH); 9.70 (s, NH). 13C-NMR (CDCl3): 27.2 (Me); 105.7 (CN); 114.4,
117.5, 123.1, 124.5, 125.0, 125.4, 128.2, 129.1, 131.9, 147.6 (Ar); 165.5, 167.1, 169.1 (triazine). EI-MS: 464
(Mþ ).
4-({4-Amino-6-[(1-bromonaphthalen-2-yl)oxy]-1,3,5-triazin-2-yl}amino)-3-fluorobenzonitrile (8f).
Yield: 0.31 g (50%). Off-white solid. M.p. 222.08 (dec.). 1H-NMR (CDCl3): 6.52 (s, NH2); 7.31–8.23
(m, 9 arom. H); 10.07 (s, NH). 13C-NMR (CDCl3): 103.6 (CN); 114.9, 119.8, 120.1, 123.1, 123.7, 126.5,

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CHEMISTRY & BIODIVERSITY – Vol. 6 (2009)
127.1, 128.6, 128.9, 129.5, 130.1, 132.6, 133.5, 148.1, 148.4 (Ar); 165.5, 168.8, 171.0 (triazine). EI-MS: 450
(Mþ ).
4-({4-[(1-Bromonaphthalen-2-yl)oxy]-6-(ethylamino)-1,3,5-triazin-2-yl}amino)-3-fluorobenzonitrile
(8g). Yield: 0.30 g (46%). Off-white solid. M.p. 264.78 (dec.). 1H-NMR (CDCl3): 1.00 (dd, J¼7.6, Me);
3.12–3.42 (m, CH2); 7.23–8.24 (m, 9 arom. H); 9.65 (s, NH). 13C-NMR (CDCl3): 14.4 (Me); 35.2 (CH2);
105.6 (CN); 113.8, 114.1, 117.6, 119.3, 123.4, 125.0, 126.0, 126.5, 127.9, 128.3, 128.4, 129.1, 147.8, 151.6, 154.0
(Ar); 165.3, 166.5, 169.8 (triazine). EI-MS: 478 (Mþ ).
4-({4-[(1-Bromonaphthalen-2-yl)oxy]-6-[(prop-2-en-1-yl)amino]-1,3,5-triazin-2-yl}amino)-3-fluo-
robenzonitrile (8h). Yield: 0.30 g (45%). Off-white solid. M.p. 198.48 (dec.). 1H-NMR (CDCl3): 3.89 (d,
J¼4.6, CH2CH¼CH2); 5.02–5.21 (m, CH2CH¼CH2); 5.84–5.91 (m, CH2CH¼CH2); 7.34–8.25 (m, 9
arom. H); 10.00 (s, 1 H, NHCH2CH¼CH2); 10.14 (s, NH). 13C-NMR (CDCl3): 43.2 (CH2CH¼CH2); 72.4
(CH2CH¼CH2); 88.5 (CH2CH¼CH2); 104.0 (CN); 114.9, 116.0, 116.6, 119.7, 119.9, 120.2, 123.6, 126.1,
127.0, 128.4, 128.6, 129.2, 129.8, 132.6, 133.1, 135.4, 144.4 (Ar); 165.7, 167.4, 170.5 (triazine). EI-MS: 490
(Mþ ).
4-({4-[(1-Bromonaphthalen-2-yl)oxy]-6-[(1-methylethyl)amino]-1,3,5-triazin-2-yl}amino)-3-fluoro-
1
benzonitrile (8i). Yield: 0.31 g (46%). Off-white solid. M.p. 232.88 (dec.). H-NMR (CDCl3): 1.12 (dd,
J¼6.8, Me2CH); 3.95–4.04 (m, Me2CH); 7.44–8.11 (m, 9 arom. H); 9.95 (s, CHMe2NH); 10.17 (s, NH).
13C-NMR (CDCl3): 22.0 (Me); 42.5 (CH); 103.8 (CN); 114.8, 119.9, 120.5, 123.5, 126.9, 128.7, 128.9, 129.5,
132.4, 133.1, 133.5, 144.5, 148.6 (Ar); 165.8, 166.4, 170.2 (triazine). EI-MS: 492 (Mþ ).
4-({4-[(1-Chloronaphthalen-2-yl)oxy]-6-(methylamino)-1,3,5-triazin-2-yl}amino)-3-fluorobenzoni-
1
trile (8j). Yield: 0.29 g (49%). Off-white solid. M.p. 265.88 (dec.). H-NMR (CDCl3): 2.82 (dd, J¼4.4,
Me); 7.49–8.26 (m, 9 arom. H); 9.97 (s, MeNH); 10.20 (s, NH). 13C-NMR (CDCl3): 27.5 (Me); 103.8
(CN); 120.0, 122.3, 123.4, 123.8, 127.1, 128.7, 128.9, 131.1, 132.3, 132.9, 133.1, 144.5, 146.6 (Ar); 166.7, 167.8,
170.1 (triazine). EI-MS: 420 (Mþ ).
4-({4-Amino-6-[(1-chloronaphthalen-2-yl)oxy]-1,3,5-triazin-2-yl}amino)-3-fluorobenzonitrile (8k).
1
Yield: 0.27 g (49%). Off-white solid. M.p. 1868 (dec.). H-NMR (CDCl3): 1.64 (s, NH2), 7.23–8.25 (m,
9 arom. H); 9.60 (s, NH). 13C-NMR (CDCl3): 105.8 (CN); 117.9, 119.1, 119.4, 121.8, 122.5, 123.3, 125.2,
126.5, 128.0, 128.4, 130.5, 131.5, 145.1, 151.9, 154.4 (Ar); 166.7, 168.2, 170.3 (triazine). EI-MS: 406 (Mþ ).
4-({4-[(1-Chloronaphthalen-2-yl)oxy]-6-(ethylamino)-1,3,5-triazin-2-yl}amino)-3-fluorobenzonitrile
1
(8l). Yield: 0.30 g (51%). Off-white solid. M.p. 231.88 (dec.). H-NMR (CDCl3): 1.01 (t, J¼6.4, Me);
3.12–3.40 (m, CH2); 3.44 (s, NHCH2); 7.29–8.28 (m, 9 arom. H); 9.63 (s, NH). 13C-NMR (CDCl3): 14.3
(Me); 38.8 (CH2); 105.5 (CN); 117.7, 119.5, 121.4, 121.8, 123.0, 123.3, 124.5, 125.4, 126.6, 127.9, 128.4,
130.5, 131.8, 146.1, 151.8, 154.3 (Ar); 165.5, 166.4, 169.9 (triazine). EI-MS: 434 (Mþ ).
4-({4-[(1-Chloronaphthalen-2-yl)oxy]-6-[(prop-2-en-1-yl)amino]-1,3,5-triazin-2-yl}amino)-3-fluo-
robenzonitrile (8m). Yield: 0.29 g (48%). Off-white solid. M.p. 240.98 (dec.). 1H-NMR (CDCl3): 3.75 (d,
J¼4.4, CH2CH¼CH2); 4.94–5.13 (m, CH2CH¼CH2); 5.74–5.85 (m, CH2CH¼CH2); 7.26–8.25 (m, 9
arom. H); 9.58 (s, NH); 9.74 (s, NH). 13C-NMR (CDCl3): 42.8 (CH2); 61.4 (CH2); 88.3 (CH); 105.7 (CN);
115.6, 117.9, 119.4, 121.8, 122.6, 123.3, 125.5, 126.5, 128.0, 128.4, 130.6, 131.8, 134.8, 146.1, 151.7, 154.2 (Ar);
166.5, 166.9, 170.2 (triazine). EI-MS: 446 (Mþ ).
4-({4-[(1-Chloronaphthalen-2-yl)oxy]-6-(propylamino)-1,3,5-triazin-2-yl}amino)-3-fluorobenzoni-
1
trile (8n). Yield: 0.30 g (49%). Off-white solid. M.p. 202.48 (dec.). H-NMR (CDCl3): 0.88 (t, J¼7.6,
MeCH2CH2); 1.44–1.58 (m, MeCH2CH2); 3.10–3.33 (m, MeCH2CH2); 7.44–8.26 (m, 9 arom. H); 9.95 (s,
NHCH3CH2CH2); 10.14 (s, NH). 13C-NMR (CDCl3): 11.3 (MeCH2CH2); 21.7 (MeCH2CH2); 42.3
(MeCH2CH2); 103.6 (CN); 119.2, 119.5, 121.9, 123.0, 123.0, 123.4, 126.5, 128.0, 128.2, 128.4, 130.7, 132.1,
132.7, 144.4, 146.6 (Ar); 165.5, 167.2, 169.9 (triazine). EI-MS: 448 (Mþ ).
Preparation of 4-{[4-Chloro-6-(4-methylphenoxy)-1,3,5-triazin-2-yl]amino}-3-fluorobenzonitrile (9).
To a stirred soln. of p-cresol (4-methylphenol; 1.22 g, 11.3 mmol) in anh. THF (100 ml) was added 6
(3.03 g, 11.3 mmol) at r.t. under N2, and stirring was continued for another 4 h at 50–608. The precipitate
was collected by filtration, washed with H2O (3ꢃ20 ml), and recrystallized from MeOH to afford 9.
Yield: 2.0 g (50%). Off-white solid. M.p. 179.68 (dec.). 1H-NMR (CDCl3): 2.27 (s, Me); 7.48–7.99 (m, 7
arom. H); 9.96 (s, NH2); 10.01 (s, NH). 13C-NMR (CDCl3): 24.6 (Me); 105.6 (CN); 109.3, 116.3, 117.5,
118.1, 119.3, 119.6, 120.2, 123.9, 127.7, 128.8, 151.9 (Ar); 155.6, 164.8, 169.6 (triazine). EI-MS: 354 (Mþ ).

CHEMISTRY & BIODIVERSITY – Vol. 6 (2009)
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General Procedure for the Preparation of 10a–10e. Amine (5.48 mmol) was added to a soln. of 9
(1.37 mmol) in 1,4-dioxane (150 ml) at r.t. under stirring. The resulting soln. was stirred at 60–708 for 1–
4 h, then precipitation took place. The solid was collected by filtration, dissolved in AcOEt (20 ml),
washed with 4% NaOH soln. (1ꢃ10 ml), sat. aq. NaHCO3 soln (3ꢃ20 ml), and brine (3ꢃ20 ml), dried
(MgSO4), and the org. layer was concentrated in vacuo at 808 to give crude products, which were
recrystallized from MeCN to afford 10a–10e.
3-Fluoro-4-{[4-(methylamino)-6-(4-methylphenoxy)-1,3,5-triazin-2-yl]amino}benzonitrile (10a).
Yield: 0.24 g (51%). Off-white solid. M.p. 209.28 (dec.). 1H-NMR (CDCl3): 2.24 (s, Me); 2.81 (s,
MeNH); 6.94–7.22 (m, 3 arom. H); 7.51–7.89 (m, 4 arom. H); 8.42 (s, MeNH); 9.06 (s, NH); 9.23 (s, NH).
13C-NMR (CDCl3): 20.8 (Me); 27.8 (MeNH); 105.2 (CN); 118.9, 119.4, 119.6, 120.5, 120.7, 124.5, 129.2,
129.3, 131.1, 133.5, 137.9 (Ar); 164.2, 164.5, 166.5 (triazine). EI-MS: 350 (Mþ ).
4-{[4-Amino-6-(4-methylphenoxy)-1,3,5-triazin-2-yl]amino}-3-fluorobenzonitrile (10b). Yield:
1
0.23 g (50%). Off-white solid. M.p. 247.78 (dec.). H-NMR (CDCl3): 2.27 (s, Me); 3.38 (s, NH2); 6.78
(s, 1 arom. H); 7.04–7.11 (m, 2 arom. H); 7.64–7.72 (m, 3 arom. H); 7.84 (s, 1 H, Ph). 13C-NMR (CDCl3):
20.8 (Me); 105.0 (CN); 118.7, 119.3, 119.5, 120.5, 129.2, 129.8, 129.8, 131.2, 131.5, 133.2 (Ar); 164.8, 167.3
(triazine). EI-MS: 336 (Mþ ).
4-{[4-(Ethylamino)-6-(4-methylphenoxy)-1,3,5-triazin-2-yl]amino}-3-fluorobenzonitrile (10c).
Yield: 0.24 g (51%). Off-white solid. M.p. >3008. 1H-NMR (CDCl3): 1.24 (t, J¼4.8, Me); 1.57 (s,
Me); 2.31–2.37 (m, CH2); 7.08–7.23 (m, 3 arom. H); 7.31–7.57 (m, 4 arom. H); 6.90 (s, EtNH); 8.74 (s,
NH). 13C-NMR (CDCl3): 20.7 (Me); 35.4 (Me); 48.3 (CH2); 105.9 (CN); 119.4, 119.7, 121.0, 125.1, 125.7,
129.5, 129.8, 131.6, 132.6, 136.3, 137.6 (Ar); 164.6, 170.2, 176.8 (triazine). EI-MS: 364 (Mþ ).
3-Fluoro-4-{[4-(4-methylphenoxy)-6-(propylamino)-1,3,5-triazin-2-yl]amino}benzonitrile (10d).
Yield: 0.26 g (51%). Off-white solid. M.p. >3008. 1H- NMR (CDCl3): 0.99 (t, J¼7.6, Me); 1.63 (s,
MeCH2CH2); 2.35–2.36 (m, MeCH2CH2); 5.09–5.23 (m, MeCH2CH2); 7.07–7.56 (m, 7 arom. H); 8.76 (s,
NH). 13C-NMR (CDCl3): 11.5 (MeCH2CH3); 20.5 (MeCH2CH2); 36.4 (MeCH2CH2); 104.5 (CN); 118.3,
119.4, 121.1, 124.4, 129.0, 129.3, 130.9, 133.7, 134.2, 134.5, 130.9, 137.8 (Ar); 163.3, 164.9, 166.3 (triazine).
EI-MS: 378 (Mþ ).
3-Fluoro-4-{[4-(4-methylphenoxy)-6-[(1-methylethyl)amino]-1,3,5-triazin-2-yl]amino}benzonitrile
(10e). Yield: 0.26 g (50%). Off-white solid. M.p. >3008. 1H-NMR (CDCl3): 1.25 (s, Me); 1.58 (d, J¼4.0,
6 H, CHMe2CH); 2.34–2.37 (m, Me2CH); 7.16–7.43 (m, 7 arom. H); 6.90 (s, NH); 8.74 (s, NH).
13C-NMR (CDCl3): 20.3 (Me); 31.9 (Me2CH); 42.4 (Me2CH); 105.6 (CN); 118.4, 119.4, 121.0, 121.9,
125.1, 126.3, 129.1, 129.8, 132.0, 133.5, 135.4, 137.3 (Ar); 164.3, 165.5, 167.4 (triazine). EI-MS: 378 (Mþ ).
Bioassay. The anti-HIVactivity and cytotoxicity were evaluated against wild-type HIV-1 strain IIIB
in MT-4 cells by the MTT method. Briefly, virus stocks were titrated in MT-4 cells and expressed as the
50% cell culture infective dose (CCID50). MT-4 Cells were suspended in culture medium (RPMI 1640
medium supplemented with 10% newborn calf serum, 2 mm l-glutamine, and 0.075% NaHCO3) at 1ꢃ
105 cells/ml and infected with HIVat a multiplicity of infection of 0.02. Immediately after virus infection,
100 ml of the cell suspension was brought into each well of a flat-bottomed microtiter tray containing
various concentrations of the test compounds. The test compounds were dissolved in DMSO at 50 mm or
higher. After incubation for 4 d at 378, the number of viable cells was determined by the MTT method.
Compounds were tested in parallel for cytotoxic effects in uninfected MT-4 cells.
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Received April 29, 2008